A placebo-controlled randomized study with testosterone in Klinefelter syndrome: beneficial effects on body composition

Abstract

Context and objective: Males with Klinefelter syndrome (KS) are typically hypogonadal with a high incidence of metabolic disease, increased body fat and mortality. Testosterone treatment of hypogonadal patients decrease fat mass, increase lean body mass and improve insulin sensitivity, but whether this extends to patients with KS is presently unknown.

Research design and methods: In a randomized, double-blind, placebo-controlled, BMI-matched cross-over study, 13 males with KS (age: 34.8 years; BMI: 26.7 kg/m2) received testosterone (Andriol®) 160 mg per day (testosterone) or placebo treatment for 6 months. Thirteen age- and BMI-matched healthy controls were recruited. DEXA scan, abdominal computed tomography (CT) scan and a hyperinsulinemic-euglycemic clamp, muscle strength and maximal oxygen uptake measurement were performed.

Results: Total lean body mass and body fat mass were comparable between testosterone-naïve KS and controls using DEXA, whereas visceral fat mass, total abdominal and intra-abdominal fat by CT was increased (P < 0.05). Testosterone decreased total body fat (P = 0.01) and abdominal fat by CT (P = 0.04). Glucose disposal was similar between testosterone-naïve KS and controls (P = 0.3) and unchanged during testosterone (P = 0.8). Free fatty acid suppression during the clamp was impaired in KS and maximal oxygen uptake was markedly lower in KS, but both were unaffected by treatment. Testosterone increased hemoglobin and IGF-I.

Conclusion: Testosterone treatment in adult males with KS for 6 months leads to favorable changes in body composition with reductions in fat mass, including abdominal fat mass, but does not change measures of glucose homeostasis.

Keywords: Klinefelter syndrome; body composition; insulin sensitivity; rare diseases/syndromes; testosterone.

Figure 1

Outline of the study design and the two separate study days.

Figure 2

(A) BMI, total and intra-abdominal fat in males with Klinefelter syndrome and controls. Under figure: Open circles indicate placebo-treated Klinefelter syndrome, closed circles indicate testosterone-treated Klinefelter syndrome and open squares indicate controls. P values are indicated in the figure. (B) Insulin sensitivity in males with Klinefelter syndrome and controls. Under figure: Round circles indicate placebo-treated KS, black circles indicate testosterone-treated KS and open squares indicate controls. There were no significant difference between groups.

Figure 3

(A) Hemoglobin and IGF-I in males with Klinefelter syndrome during placebo or testosterone treatment and in controls. (B) FFA, insulin and glucagon at baseline and during clamp conditions. Under figure: Open circles indicate placebo-treated KS, closed circles indicate testosterone-treated KS and open squares indicate controls.